Several arenaviruses cause hemorrhagic fever others) and Africa (Lassa virus), and are classil antiviral with activity against these agents, riba\ infections and has significant toxicity. The Toya 705, with broad -spectrum activity against a nun 705 prevents death in the Pichinde virus (PICV initiated at late stages of infection. T-705 is cur influenza virus infections, so the safety of the c goal of this project is to advance the developrm facilitated by the completion of the following spi dependent RNA-oolvmerase (RdRp) is the prirr Program Director (Last, First, Middle): Belisle, John T. (HF) in endemic regions of South America (Junin virus and fied as Category A pathogens by the NIAID. The only licensed /irin, has had mixed success in the treatment of severe ma Chemical Co. has developed a pyrazine derivative, Tnber of RNA viruses, including arenaviruses. Remarkably, T- ) hamster model of arenaviral HF even when treatment is rently in clinical trials in the US and Japan for the treatment of ompound is being comprehensively addressed. The long-term ;nt of T-705 for the treatment of arenaviral HFs. This will be scific aims. 1. Determine if the inhibition of the RNAiarv T-705 mechanism of action aqainst arenaviruses. T-705 acts as a nucleoside analog specifically inhibiting the influenza polymerase. RdRp domains are attractive drug targets since they are not present in the host and are conserved among RNA viruses. Several strategies will be used to investigate the RdRp of the arenaviruses as the main target of T-705 inhibition, including time-of-addition and nucleotide/nucleoside competition studies, replicon-based inhibition assays and the examination of resistant viruses. 2. Determine T-705 distribution and pharmacokinetics (PK) during advanced PICV infection in hamsters and efficacv in the auinea piq (GP) PICV infection model. Tissue distribution and PK will be determined in infects infection can diminish kidney function, altering experiments in PICV-challenged GPs will facilit to the more costly Junin virus (JUNV) GP effice nonhuman primate models of JUNV infection. F demonstrable efficacy in GP and nonhuman pr agents, which more faithfully model human dise Research Focus on Viral Therapeutics, and wil }d and uninfected hamsters since pantropic arenaviral normal biodistribution and PK profiles. T-705 efficacy ate the selection of optimal treatment regimens for transition cv studies. 3. Evaluate the efficacv of T-705 in GP and :DA approval for use against arenaviral HF agents will require mate models based on infection with authentic arenaviral HF jase. This research project fits within the RMRCE Integrated interact directly with RPs 3.1, 3.4, 3.6, and 3.7.